PDE IV inhibiting 2-cyanoiminoimidazole derivatives

ABSTRACT

The present invention concerns 2-cyanoiminoimidazole derivatives having the formula ##STR1## the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein R 1  and R 2  each independently are hydrogen; C 1-6  alkyl; difluoromethyl; trifluoromethyl; C 3-6  cycloalkyl; a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen; indanyl; 6,7-dihydro-5H-cyclopentapyridinyl; bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl; C 1-6  alkylsulfonyl; arylsulfonyl; or substituted C 1-10  alkyl; R 3  is hydrogen, halo or C 1-6  alkyloxy; R 4  is hydrogen; halo; C 1-6  alkyl; trifluoromethyl; C 3-6  cycloalkyl; carboxyl; C 1-4  alkyloxycarbonyl; C 3-6  cycloalkylaminocarbonyl; aryl; Het 1  ; or substituted C 1-6  alkyl; or R 4  is --O--R 7  or --NH--R 8  ; R 5  is hydrogen, halo, hydroxy, C 1-6  alkyl or C 1-6  alkyloxy; R 6  is a hydrogen or C 1-4  alkyl; or R 4  and R 6 , or R 4  and R 5  taken together may form a bivalent radical; --A--B-- is --CR 10  ═CR 11  -- or --CHR 10  --CHR 11  --; L is hydrogen; C 1-6  alkyl; C 1-6  alkylcarbonyl; C 1-6  alkyloxycarbonyl; substituted C 1-6  alkyl; C 3-6  alkenyl; substituted C 3-6  alkenyl; piperidinyl; substituted piperidinyl; C 1-6  alkylsulfonyl or arylsulfonyl; having PDE IV and cytokine inhibiting activity. The invention also relates to processes for preparing the compounds of formula (I) and pharmaceutical compositions thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a National Stage application under 35 U.S.C. 371 ofPCT/EP97/05322 filed Sep. 24, 1997, which claims priority from EP96.202.749.6, filed Oct. 2, 1996.

The present invention concerns 2-cyanoiminoimidazole derivatives havingphosphodiesterase IV (PDE IV) and cytokine inhibiting activity and theirpreparation; it further relates to compositions comprising them, as wellas their use as a medicine.

WO 95/05386, published on Feb. 23, 1995 by Smithkline BeechamCorporation, discloses phenethylamine derivatives, such asN-[2-(3-cyclopentyloxy-3-methoxyphenyl)ethyl]imidodicarbamide andN'-cyano-1-[2-(3-cyclopentyloxy-4-methoxyphenyl)ethyl]carboximidamide,useful for treating phosphodiesterase IV related disease states. It alsogenerically discloses phenethylamine derivatives containing acyanoguanidine moiety.

The compounds of the present invention differ structurally fromart-known PDE IV inhibitors by the fact that they invariably contain a2-cyanoiminoimidazole moiety. They have therapeutical utility in thetreatment of disease states related to an abnormal enzymatic orcatalytic activity of PDE IV, and/or disease states related to aphysiologically detrimental excess of cytokines, in particular allergic,atopic and inflammatory diseases. The present compounds also have fewgastro-intestinal side-effects which are often associated with PDE IVinhibitors.

The present invention concerns 2-cyanoiminoimidazole derivatives havingthe formula ##STR2## the N-oxide forms, the pharmaceutically acceptableacid or base addition salts and the stereochemically isomeric formsthereof, wherein: R¹ and R² each independently are hydrogen; C₁₋₆ alkyl;difluoromethyl; trifluoromethyl; C₃₋₆ cycloalkyl; a saturated 5-, 6- or7-membered heterocycle containing one or two heteroatoms selected fromoxygen, sulfur or nitrogen; indanyl; 6,7-dihydro-5H-cyclopentapyridinyl;bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl; C₁₋₆ alkylsulfonyl;arylsulfonyl; or C₁₋₁₀ alkyl substituted with one or two substituentseach independently selected from aryl, pyridinyl, thienyl, furanyl,indanyl, 6,7-dihydro-5H-cyclopentapyridinyl, C₃₋₇ cycloalkyl and asaturated 5-, 6- or 7-membered heterocycle containing one or twoheteroatoms selected from oxygen, sulfur or nitrogen;

R³ is hydrogen, halo or C₁₋₆ alkyloxy;

R⁴ is hydrogen; halo; C₁₋₆ alkyl; trifluoromethyl; C₃₋₆ cycloalkyl;carboxyl; C₁₋₄ alkyloxycarbonyl; C₃₋₆ cycloalkylaminocarbonyl; aryl;Het¹ ; or C₁₋₆ alkyl substituted with cyano, amino, hydroxy, C₁₋₄alkylcarbonylamino, aryl or Het¹ ; or R⁴ is a radical of formula:

    --O--R.sup.7                                               (a- 1); or

    --NH--R.sup.8                                              (a- 2);

wherein R⁷ is hydrogen; C₁₋₆ alkyl; C₁₋₆ alkyl substituted with hydroxy,carboxyl, C₁₋₄ alkyloxycarbonyl, amino, mono- or di(C₁₋₄ alkyl)amino,Het¹ or aryl;

R⁸ is hydrogen; C₁₋₆ alkyl; C₁₋₄ alkylcarbonyl; C₁₋₆ alkyl substitutedwith hydroxy, carboxyl, C₁₋₄ alkyloxycarbonyl, amino, mono- or di(C₁₋₄alkyl)amino, Het¹ or aryl;

R⁵ is hydrogen, halo, hydroxy, C₁₋₆ alkyl or C₁₋₆ alkyloxy; or

R⁴ and R⁵ taken together may form a bivalent radical of formula:

    --(CH.sub.2).sub.n --                                      (b-1);

    --CH.sub.2 --CH.sub.2 --O--CH.sub.2 --CH.sub.2 --          (b-2);

    --CH.sub.2 --CH.sub.2 --N(R.sup.9)--CH.sub.2 --CH.sub.2 -- (b-3); or

    --CH.sub.2 --CH═CH--CH.sub.2 --                        (b-4);

wherein n is 2, 3, 4 or 5;

R⁹ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl or p-toluenesulfonyl;

R⁶ is a hydrogen or C₁₋₄ alkyl; or

R⁴ and R⁶ taken together may form a bivalent radical of formula--(CH₂)_(m) --;

wherein m is 1, 2, 3 or 4;

--A--B-- is a bivalent radical of formula:

    --CR.sup.10 ═CR.sup.11 --                              (c-1); or

    --CHR.sup.10 --CHR.sup.11 --                               (c-2);

wherein each R¹⁰ and R¹¹ independently is hydrogen or C₁₋₄ alkyl; and

L is hydrogen; C₁₋₆ alkyl; C₁₋₆ alkylcarbonyl; C₁₋₆ alkyloxycarbonyl;C₁₋₆ alkyl substituted with one or two substituents selected from thegroup consisting of hydroxy, C₁₋₄ alkyloxy, C₁₋₄ alkyloxycarbonyl, mono-and di(C₁₋₄ alkyl)amino, aryl and Het² ; C₃₋₆ alkenyl; C₃₋₆ alkenylsubstituted with aryl; piperidinyl; piperidinyl substituted with C₁₋₄alkyl or arylC₁₋₄ alkyl; C₁₋₆ alkylsulfonyl or arylsulfonyl;

aryl is phenyl or phenyl substituted with one, two or three substituentsselected from halo, hydroxy, C₁₋₄ alkyl, C₁₋₄ alkyloxy, C₃₋₆ cycloalkyl,trifluoromethyl, amino, nitro, carboxyl, C₁₋₄ alkyloxycarbonyl and C₁₋₄alkylcarbonylamino;

Het¹ is pyridinyl; pyridinyl substituted with C₁₋₄ alkyl; furanyl;furanyl substituted with C₁₋₄ alkyl; thienyl; thienyl substituted withC₁₋₄ alkylcarbonylamino; hydroxypyridinyl, hydroxypyridinyl substitutedwith C₁₋₄ alkyl or C₁₋₄ alkoxy-C₁₋₄ alkyl; imidazolyl; imidazolylsubstituted with C₁₋₄ alkyl; thiazolyl; thiazolyl substituted with C₁₋₄alkyl; oxazolyl; oxazolyl substituted with C₁₋₄ alkyl; isoquinolinyl;isoquinolinyl substituted with C₁₋₄ alkyl; quinolinonyl, quinolinonylsubstituted with C₁₋₄ alkyl; morpholinyl; piperidinyl; piperidinylsubstituted with C₁₋₄ alkyl, C₁₋₄ alkyloxycarbonyl or arylC₁₋₄ alkyl;piperazinyl; piperazinyl substituted with C₁₋₄ alkyl, C₁₋₄alkyloxycarbonyl or arylC₁₋₄ alkyl; and

Het² is morpholinyl; piperidinyl; piperidinyl substituted with C₁₋₄alkyl or arylC₁₋₄ alkyl; piperazinyl; piperazinyl substituted with C₁₋₄alkyl or arylC₁₋₄ alkyl; pyridinyl; pyridinyl substituted with C₁₋₄alkyl; furanyl; furanyl substituted with C₁₋₄ alkyl; thienyl or thienylsubstituted with C₁₋₄ alkyl or C₁₋₄ alkylcarbonylamino.

Some of the compounds of formula (I) may also exist in their tautomericforms. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.In particular, compounds of formula (I) wherein L is hydrogen may existin their corresponding tautomeric form.

In R¹ and R², the saturated 5-, 6- or 7-membered heterocycles containingone or two heteroatoms selected from oxygen, sulfur or nitrogen maysuitably be selected from heterocycles such as, for example,tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, morpholinyl, piperidinyl,piperazinyl and tetrahydropyranyl. Said heterocyclic radicals areattached to the oxygen atom or the C₁₋₁₀ alkyl radical by any carbonatom or, where appropriate, by a nitrogen atom.

Also in R¹ and R², the term 6,7-dihydro-5H-cyclopentapyridinyl, alsonamed 6,7-dihydro-5H-pyrindinyl, is meant to represent6,7-dihydro-5H-cyclopenta[b]pyridine or6,7-dihydro-5H-cyclopenta[c]pyridinyl and may be attached to theremainder of the molecule by any of the aliphatic or aromatic carbonatoms.

As used herein the term halo is generic to fluoro, chloro, bromo andiodo; the term C₁₋₄ alkyl is meant to include straight chained orbranched saturated hydrocarbons having from 1 to 4 carbon atoms such as,for example, methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl,2-methylpropyl and butyl; the term C₁₋₆ alkyl is meant to include C₁₋₄alkyl and the higher homologues thereof having 5 or 6 carbon atoms suchas, for example, 2-methylbutyl, pentyl, hexyl and the like; the termC₁₋₆ alkyl is meant to include C₂₋₆ alkyl and the lower homologuethereof having 1 carbon atom such as, for example, methyl; C₁₋₁₀ alkylis meant to include C₁₋₆ alkyl and the higher homologues thereof havingfrom 7 to 10 carbon atoms such as, for example, heptyl, octyl, nonyl,decyl, 1-methylhexyl, 2-methylheptyl and the like; the term C₃₋₆ alkenyldefines straight and branch chained hydrocarbon radicals containing onedouble bond and having from 3 to 6 carbon atoms such as, for example,2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl,3-methyl-2-butenyl and the like; and the carbon atom of said C₃₋₆alkenyl being connected to a nitrogen atom preferably is saturated; theterm C₃₋₆ cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl; the term C₃₋₇ cycloalkyl is meant to include C₃₋₆cycloalkyl and cycloheptyl; the term C₁₋₄ alkanediyl is meant to includestraight chained and branched saturated bivalent hydrocarbon radicalshaving from 1 to 4 carbon atoms, such as, for example, methylene,1,2-ethanediyl, 1,1-ethanediyl, 1,3-propanediyl, 1,2-propanediyl,1,4-butanediyl, 2-methyl-1,3-propanediyl and the like.

As used in the foregoing definitions and hereinafter, haloC₁₋₄alkanediyl is defined as mono- or polyhalosubstituted C₁₋₄ alkanediyl,in particular C₁₋₄ alkanediyl substitituted with one or more fluoratoms.

The pharmaceutically acceptable acid addition salts as mentionedhereinabove are meant to comprise the acid addition salt forms which canconveniently be obtained by treating the base form of the compounds offormula (I) with appropriate acids such as inorganic acids, for example,hydrohalic acid, e.g. hydrochloric or hydrobromic, sulfuric, nitric,phosphoric and the like acids; or organic acids, such as, for example,acetic, hydroxy-acetic, propanoic, lactic, pyruvic, oxalic, malonic,succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids. Conversely, said acidaddition salt forms can be converted in the free base forms by treatmentwith an appropriate base.

The compounds of formula (I) containing an acidic proton may also beconverted into their non-toxic metal or amine addition salt forms bytreatment with appropriate organic and inorganic bases. Appropriate basesalt forms comprise, for example, the ammonium salts, the alkali andearth alkaline metal salts, e.g. the lithium, sodium, potassium,magnesium, calcium salts and the like, salts with organic bases, e.g.the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts withamino acids such as, for example, arginine, lysine and the like.

The term addition salt also comprises the hydrates and solvent additionforms which the compounds of formula (I) are able to form. Examples ofsuch forms are e.g. hydrates, alcoholates and the like.

The N-oxide forms of the compounds of formula (I) are meant to comprisethose compounds of formula (I) wherein one or several nitrogen atoms areoxidized to the so-called N-oxide.

The term "stereochemically isomeric forms" as used hereinbefore definesall the possible isomeric forms which the compounds of formula (I) maypossess. Unless otherwise mentioned or indicated, the chemicaldesignation of compounds denotes the mixture of all possiblestereochemically isomeric forms, said mixtures containing alldiastereomers and enantiomers of the basic molecular structure. More inparticular, stereogenic centers may have the R- or S-configuration, andthe ═N--CN and substituted C₃₋₆ alkenyl moieties may have the E- orZ-configuration.

Whenever used hereinafter, the term compounds of formula (I) is meant toinclude also the N-oxide forms, the pharmaceutically acceptable acid orbase addition salts and all stereoisomeric forms.

Some of the compounds of formula (I) and some of the intermediates inthe present invention may contain an asymmetric carbon atom. Purestereochemically isomeric forms of said compounds and said intermediatescan be obtained by the application of art-known procedures. For example,diastereoisomers can be separated by physical methods such as selectivecrystallization or chromatographic techniques, e.g. counter currentdistribution, liquid chromatography and the like methods. Enantiomerscan be obtained from racemic mixtures by first converting said racemicmixtures with suitable resolving agents such as, for example, chiralacids, to mixtures of diastereomeric salts or compounds; then physicallyseparating said mixtures of diastereomeric salts or compounds by, forexample, selective crystallization or chromatographic techniques, e.g.liquid chromatography and the like methods; and finally converting saidseparated diastereomeric salts or compounds into the correspondingenantiomers. Pure stereochemically isomeric forms may also be obtainedfrom the pure stereochemically isomeric forms of the appropriateintermediates and starting materials, provided that the interveningreactions occur stereospecifically. The pure and mixed stereochemicallyisomeric forms of the compounds of formula (I) are intended to beembraced within the scope of the present invention.

An alternative manner of separating the enantiomeric forms of thecompounds of formula (I) and intermediates involves liquidchromatography, in particular liquid chromatography using a chiralstationary phase.

A special group of compounds includes those compounds of formula (I)wherein R¹ and R² each independently are hydrogen; C₁₋₆ alkyl;difluoromethyl; trifluoromethyl; C₃₋₆ cycloalkyl; a saturated 5-, 6- or7-membered heterocycle containing one or two heteroatoms selected fromoxygen, sulfur or nitrogen; indanyl; bicyclo[2.2.1]-2-heptenyl;bicyclo[2.2.1]heptanyl; C₁₋₆ alkylsulfonyl; arylsulfonyl; or C₁₋₁₀ alkylsubstituted with one or two substituents each independently selectedfrom aryl, pyridinyl, thienyl, furanyl, C₃₋₇ cycloalkyl and a saturated5-, 6- or 7-membered heterocycle containing one or two heteroatomsselected from oxygen, sulfur or nitrogen.

Interesting compounds are those compounds of formula (I) wherein R¹ andR² are each independently C₁₋₆ alkyl; C₃₋₆ cycloalkyl; difluoromethyl; asaturated 5-, 6- or 7-membered heterocycle containing one or twoheteroatoms selected from oxygen, sulfur or nitrogen, which preferablyis tetrahydrofuranyl; indanyl; or C₁₋₁₀ alkyl substituted with aryl,indanyl, 6,7-dihydro-5H-cyclopentapyridinyl or C₃₋₆ cycloalkyl.

Also interesting are those compounds of formula (I) wherein R⁵ ishydrogen and R⁴ is hydrogen, hydroxy or C₁₋₆ alkyl, more in particular,R⁴ is methyl.

Another interesting group are those compounds of formula (I) wherein Lis hydrogen, C₁₋₆ alkyloxycarbonyl, or C₁₋₆ alkyl substituted with oneor two phenyl rings.

Particular compounds are those compounds of formula (I) wherein R¹ iscyclopentyl, tetrahydrofuranyl, cyclopropylmethyl, 5-phenylpentyl,2-indanylethyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl or indanyl; and R²is methyl or difluoromethyl.

Preferred compounds are those particular compounds wherein R³, R⁵, R⁶,R¹⁰, R¹¹ and L are hydrogen.

Most preferred are the following compounds:

[1-[2-[4-(difluoromethoxy)-3-[(tetrahydro-3-furanyl)oxy]phenyl]propyl]-1,3-dihydro-2H-imidazol-2-ylidene]cyanamide;and

[1-[2-[4-(methoxy)-3-[(1,3-dihydro-2H-inden-2-yl)oxy]phenyl]propyl]-1,3-dihydro-2H-imidazol-2-ylidene]cyanamide;their N-oxides, their stereochemically isomeric forms and theirpharmaceutically acceptable additon salts.

Whenever used hereinafter, R¹ to R¹¹, Y, --A--B-- and L are defined asunder formula (I) unless otherwise indicated.

Compounds of formula (I) wherein --A--B-- is a radical of formula (c-1)and L is hydrogen, said compounds being represented by formula (I-a-1),can conveniently be prepared by cyclization of an intermediate offormula (II) or a functional derivative thereof in the presence of asuitable acid such as, for example, hydrochloric acid. ##STR3##

Said cyclization may be performed in a reaction inert solvent such as,for example, tetrahydrofuran or 1,4-dioxane or a mixture thereof.Stirring and heating may enhance the rate of the reaction.

In this and the following preparations, the reaction products may beisolated from the reaction medium and, if necessary, further purifiedaccording to methodologies generally known in the art such as, forexample, extraction, crystallization, trituration and chromatography.

In particular, compounds of formula (I-a-1) wherein R⁵ is hydroxy, saidcompounds being represented by formula (I-a-1-1), may be prepared bycyclization of an intermediate of formula (II-1) wherein P is hydrogenor, preferably, is a trimethylsilyl protecting group or a functionalderivative thereof, in a manner analogous to the one described for thepreparation of a compound of formula (I-a-1) from an intermediate offormula (II). ##STR4##

Compounds of formula (I) wherein --A--B-- is a radical of formula (c-2)and L is hydrogen, said compounds being represented by formula (I-a-2),can be obtained by cyclization of an intermediate of formula (III) or afunctional derivative thereof in the presence of a suitable reagent suchas, for example, dimethyl cyanocarbonimidodithioate or diphenylN-cyanocarbonimidate. ##STR5##

Alternatively, compounds of formula (I) may be prepared by reacting anorganometallic intermediate of formula (IV), wherein M is an appropriatemetal ion or metalcomplex ion such as, for example, Li⁺, (MgBr)⁺, B(OH)₂⁺ or Sn(CH₃)₃ ⁺, in a reaction-inert solvent with a suitable2-cyanoiminoimidazole derivative of formula (V) wherein W¹ is a reactiveleaving group such as, for example, a halogen. In case R⁴ and R⁵ aretaken together and form a radical of formula (b-1), (b-2), (b-3) or(b-4), W¹ may also be a cyanide moiety provided that the intermediate offormula (IV) is a Grignard reagent. ##STR6##

Said reaction may be performed in a reaction-inert solvent such as, forexample, dimethoxyethane, tetrahydrofuran or diethylether. Stirring andheating may enhance the rate of the reaction. In case intermediates offormula (V), wherein L is replaced by a suitable protecting group, areused in said reaction, compounds of formula (I) wherein L is hydrogen,said compounds being represented by compounds of formula (I-a), may beobtained using art-known deprotection reactions.

The compounds of formula (I) can also be converted into each otherfollowing art-known procedures of functional group transformation.

For example, compounds of formula (I) wherein L is other than hydrogen,said compounds being represented by formula (I-b), may be prepared byreacting a compound of formula (I-a) with L'--W² (VI), wherein L' is thesame as L defined under formula (I) but other than hydrogen and W² is areactive leaving group such as, for example, a halogen atom. ##STR7##

Also art-known addition reactions may be used to convert compounds offormula (I-a) into compounds of formula (I-b).

The compounds of formula (I) may also be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I) with3-phenyl-2-(phenylsulfonyl)oxaziridine or with an appropriate organic orinorganic peroxide. Appropriate inorganic peroxides comprise, forexample, hydrogen peroxide, alkali metal or earth alkaline metalperoxides, e.g. sodium peroxide, potassium peroxide; appropriate organicperoxides may comprise peroxy acids such as, for example,benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid,e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g.peroxoacetic acid, alkylhydroperoxides, e.g. t-butyl hydroperoxide.Suitable solvents are, for example, water, lower alkanols, e.g. ethanoland the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone,halogenated hydrocarbons, e.g. dichloromethane, and mixtures of suchsolvents.

Intermediates mentioned hereinabove may be prepared following art-knowntechniques.

In particular, intermediates of formula (II) may be prepared by firstreacting an amine of formula (VII) with dimethylcyanocarbonimidodithioate or diphenyl cyanocarbonimidate or a functionalderivative thereof. Said reaction can conveniently be performed in areaction inert solvent such as, for example, dichloromethane, benzene ortoluene, optionally cooled on an ice-bath, and in the presence of a basesuch as, for example, N,N-diethylethanamine or sodiumbicarbonate. Thethus obtained intermediate may be subsequently reacted with anintermediate of formula (VIII) or a functional derivative thereof, toform an intermediate of formula (II). Said reaction can conveniently beperformed in a reaction inert solvent such as, for example, 1,4-dioxane,in the presence of a base such as, for example, N,N-diethylethanamine,and optionally in the presence of a catalyst such as, for example,N,N-dimethyl-pyridinamine. Stirring and elevated temperatures mayenhance the rate of the reaction. ##STR8##

Alternatively, the above reaction may be performed in reverse order,i.e. first react an intermediate of formula (VIII with dimethylcyanocarbonimidodithioate or diphenyl cyanocarbonimidate or a functionalderivative thereof, and subsequently react the thus formed intermediatewith an amine of formula (VII).

Intermediates of formula (III) wherein R¹¹ is hydrogen, saidintermediates being represented by formula (III-1), may be prepared byfirst reacting an amine of formula (VII) with a cyano derivative offormula (IX) wherein W³ is an appropriate leaving group such as, forexample, a halogen, in the presence of a base such as, for example,sodiumcarbonate, in a reaction-inert solvent such as, for example,N,N-dimethylformamide. Subsequently, the cyanide moiety in the thusformed intermediate may be reduced using a suitable reducing agent suchas, for example, lithium aluminium hydride or hydrogen in the presenceof a catalyst such as, for example, Raney nickel, thus obtaining anintermediate of formula (III-1). ##STR9##

Some of the intermediates of formula (VII) are described in WO 92/00968,WO 93/15044 and WO 93/15045.

In particular, intermediates of formula (VII) may be prepared byreacting an intermediate of formula (X) wherein W⁴ is a suitable leavinggroup such as, for example, a halogen with an intermediate of formula(XI) wherein M is an appropriate metal ion or metalcomplex ion such as,for example, Li⁺ or (MgBr)⁺, and P is a suitable protecting group suchas, for example, (1,1-dimethylethyl)oxycarbonyl. The thus obtainedprotected intermediates of formula (VII) may subsequently be deprotectedby art-known techniques such as, for example, acid hydrolysis. ##STR10##

Intermediates of formula (VII) wherein R⁶ is hydrogen, saidintermediates being represented by formula (VII-1), may be prepared byreducing the unsaturated carbon-nitrogen bond in the intermediates offormula (XII) with a suitable reducing agent such as, for example,borane-tetrahydrofuran-complex, lithium aluminium hydride, or hydrogenin the presence of a catalyst such as, for example, Raney nickel. Thecyanide moiety in the intermediates of formula (XII) may also bereplaced by a functional derivative thereof such as, for example, anoxime moiety. ##STR11##

Some of the intermediates of formula (XII) are described in WO 92/00968,WO 93/15044 and WO 93/15045.

In particular, intermediates of formula (XII) wherein R⁵ is a protectedhydroxy group and R⁴ is hydrogen, said intermediates being representedby formula (XII-1), can conveniently be prepared by reacting an aldehydeof formula (XIII) with a reagent of formula (XIV) or a functionalderivative thereof wherein P is a protective group such as, for example,trimethylsilyl and the like. in a reaction-inert solvent such as, forexample, dichloromethane, and in the presence of a catalytic amount ofZnI₂ or a functional derivative thereof. Said intermediates of formula(XII-1) may be further reacted as described hereinabove to finally forma compound of formula (I) wherein R⁵ is hydroxy. ##STR12##

The aldehydes of formula (XIII) can conveniently be prepared analogousto the reaction procedure described by Mitsunobu Oyo in Synthesis, 1-28,1981.

Some of the compounds of formula (I) and some of the intermediates inthe present invention contain at least one asymmetric carbon atom. Purestereochemically isomeric forms of said compounds and said intermediatescan be obtained by the application of art-known procedures. For example,diastereoisomers can be separated by physical methods such as selectivecrystallization or chromatographic techniques, e.g. counter currentdistribution, liquid chromatography and the like methods. Enantiomerscan be obtained from racemic mixtures by first converting said racemicmixtures with suitable resolving agents such as, for example, chiralacids, to mixtures of diastereomeric salts or compounds; then physicallyseparating said mixtures of diastereomeric salts or compounds by, forexample, selective crystallization or chromatographic techniques, e.g.liquid chromatography and the like methods; and finally converting saidseparated diastereomeric salts or compounds into the correspondingenantiomers.

Pure stereochemically isomeric forms of the compounds of formula (I) mayalso be obtained from the pure stereochemically isomeric forms of theappropriate intermediates and starting materials, provided that theintervening reactions occur stereo-specifically. The pure and mixedstereochemically isomeric forms of the compounds of formula (I) areintended to be embraced within the scope of the present invention.

The compounds of formula (I), the N-oxide forms, pharmaceuticallyacceptable acid or base addition salts and the stereochemically isomericforms thereof, are potent inhibitors of the phosphodiesterase (PDE)isoenzymes of family IV (cAMP-specific family).

cAMP (adenosine cyclic 3',5'-monophosphate) is a key second messenger,the concentration of which affects particular cell activities throughactivation of enzymes such as kinases. PDE IV is known to hydrolyse cAMPto its corresponding inactive 5'-monophosphate metabolite. Hence,inhibition of PDE IV leads to an elevation of cAMP levels in particularcells such as the respiratory smooth muscle cell and in a wide varietyof inflammatory cells, i.e. certain lymphocytes, e.g. basophils,neutrophils and eosinophils, monocytes and mast-cells. A number ofallergic, atopic and inflammatory diseases are deemed to be caused byhigher-than-normal PDE IV concentrations which result in low cAMP levelsand hypersensitivity of the thus affected cells for excitatory stimuli.(Examples of said hypersensitivity are for example, excessive histaminerelease from basophils and mast cells or excessive superoxide anionradical formation by eosinophils.) Hence, the present compounds havingpotent phosphodiesterase IV inhibitory properties are deemed usefulagents in alleviating and/or curing allergic, atopic and inflammatorydiseases. The functional effects of PDE IV inhibitors are e.g.respiratory smooth muscle relaxation, bronchodilation, plateletaggregation inhibition and inhibition of white blood cell mediatorrelease. Examples of allergic diseases are bronchial asthma, cheilitis,conjunctivitis, contact dermatitis and eczema, irritable bowel disease,deshydroform eczema, urticaria, vasculitis, vulvitis; examples of atopicdiseases are dermatitis and eczema, winterfeet, asthma, allergicrhinitis; and related afflictions are, for example, psoriasis and otherhyperproliferative diseases.

The present invention thus also relates to compounds of formula (I) asdefined hereinabove for use as a medicine, in particular for use as amedicine for treating atopic diseases or as an anti-asthmatic medicine.Thus the compounds of the present invention may be used for themanufacture of a medicament for treating atopic or asthmatic diseases,more in particular atopic dermatitis.

The PDE IV inhibitory activity of the compounds of formula (I) may bedemonstrated in the test "Inhibition of recombinant human mononuclearlymphocyte (MNL) phosphodiesterase type IV B produced in insect cellswith a baculovirus vector". Several in vivo and in vitro tests may beused to demonstrate the usefulness of the compounds of formula (I) intreating the described allergic, atopic and inflammatory diseases. Suchtests are for instance, "Bronchoconstriction of the guinea pig tracheain vitro", "Bronchoconstriction of the guinea pig trachea in vivo" andthe in vivo tests "Arachidonic acid induced pinnal inflammation inmice", "TPA induced ear inflammation in mice", and "Delayed typehypersensitivity in mice".

Further, the present compounds have only very low inhibitory activity onthe phosphodiesterase isoenzymes of family III (cGMP-inhibited family).Inhibition of, in particular, PDE III leads to an elevation of cAMP inthe cardiac muscle, thereby causing effects on the contractile force ofthe heart as well as on the relaxation of the heart. In the treatment ofthe described allergic, atopic and inflammatory diseases, cardiovasculareffects clearly are undesired. Hence, as the present compounds inhibitPDE IV at much lower concentrations as they inhibit PDE III, theirtherapeutic use may be adjusted to avoid cardiovascular side-effects.

Art-known PDE IV inhibitors often cause adverse gastro-intestinal sideeffects. Most of the present compounds, however, have few effects on thegastro-intestinal tract, which may be demonstrated in the test "Gastricemptying of a caloric meal in rats".

The designation PDE III and IV as used herein refers to theclassification by J. A. Beavo and D. H. Reifsnyder, TIPS Reviews, April1990, pp. 150-155.

The compounds of the present invention also have cytokine inhibitoryactivity. A cytokine is any secreted polypeptide that affects thefunction of other cells by modulating interactions between cells in theimmune or inflammatory response. Examples of cytokines are monokines andlymphokines and they may be produced by a wide variety of cells. Forinstance, a monokine is generally referred to as being produced andsecreted by a mononuclear cell, such as a macrophage and/or monocyte butmany other cells produce monokines, such as natural killer cells,fibroblasts, basophils, neutrophils, endothelial cells, brainastrocytes, bone marrow stromal cells, epideral keratinocytes, andβ-lymphocytes. Lymphokines are generally referred to as being producedby lymphocyte cells. Examples of cytokines include Interleukin-1 (IL-1),Interleukin-2 (IL-2), Interleukin-6 (IL-6), Interleukin-8 (IL-8),alpha-Tumor Necrosis Factor (αTNF) and beta-Tumor Necrosis Factor(βTNF).

The cytokine specifically desired to be inhibited is αTNF. Excessive orunregulated TNF production is implicated in mediating or exacerbating anumber of diseases including rheumatoid arthritis, rheumatoidspondylitis, osteoarthritis, gouty arthritis, and other arthriticconditions; sepsis, septic shock, endotoxic shock, gram negative sepsis,toxic shock syndrome, adult respiratory distress syndrome, cerebralmalaria, chronic pulmonary inflammatory disease, silicosis, pulmonarysarcoidosis, bone resorption diseases, reperfusion injury, graft versushost reaction, allograft rejections, fever and myalgias due toinfection, such as influenza, cachexia secondary to infection ormalignancy, cachexia secondary to acquired immune deficiency syndrome(AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissueformation, Crohn's disease, ulcerative colitis, or pyresis.

The cytokine inhibitory activity of the compounds of formula (I), suchas the inhibition of αTNF production, may be demonstrated in the invitro test "Cytokine production in human whole blood cultures".

In addition, the compounds of the present invention are expected to showno or little endocrinological side-effects. This may be evidenced by,for instance, the "Testosterone in vivo" test, the "In vitro inhibitionof the aromatase activity"-test and the "In vivo inhibition of thearomatase activity"-test.

In view of their useful PDE IV and cytokine inhibiting properties, thesubject compounds may be formulated into various pharmaceuticalcompositions for administration purposes comprising a pharmaceuticallyacceptable carrier, and as active ingredient a therapeutically effectiveamount of a compound of formula (I). To prepare the pharmaceuticalcompositions of this invention, a therapeutically effective amount ofthe particular compound, in base or acid addition salt form, as theactive ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which may take a wide variety offorms depending on the form of preparation desired for administration.These pharmaceutical compositions are desirably in unitary dosage formsuitable, preferably, for administration orally, rectally, topically,percutaneously, by inhalation or by parenteral injection. For example,in preparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed, such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs and solutions: orsolid carriers such as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets. Because of their ease in administration, tabletsand capsules represent the most advantageous oral dosage unit form, inwhich case solid pharmaceutical carriers are obviously employed. Forparenteral compositions, the carrier will usually comprise sterilewater, at least in large part, though other ingredients, for example, toaid solubility, may be included. Injectable solutions, for example, maybe prepared in which the carrier comprises saline solution, glucosesolution or a mixture of saline and glucose solution. Injectablesuspensions may also be prepared in which case appropriate liquidcarriers, suspending agents and the like may be employed. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewettable agent, optionally combined with suitable additives of anynature in minor proportions, which additives do not cause anysignificant deleterious effects on the skin. Said additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as a spot-onor as an ointment. As appropriate compositions for topical applicationthere may be cited all compositions usually employed for topicallyadministering drugs e.g. creams, gellies, dressings, shampoos,tinctures, pastes, ointments, salves, powders and the like. Applicationof said compositions may be by aerosol, e.g. with a propellent such asnitrogen, carbon dioxide, a freon, or without a propellent such as apump spray, drops, lotions, or a semisolid such as a thickenedcomposition which can be applied by a swab. In particular, semisolidcompositions such as salves, creams, gellies, ointments and the likewill conveniently be used.

In order to enhance the solubility and/or the stability of the compoundsof formula (I) in pharmaceutical compositions, it can be advantageous toemploy α-, β- or γ-cyclodextrins or their derivatives, in particularhydroxyalkyl substituted cyclodextrins, e.g.2-hydroxypropyl-β-cyclodextrin. Also co-solvents such as alcohols mayimprove the solubility and/or the stability of the compounds of formula(I) in pharmaceutical compositions. In the preparation of aqueouscompositions, addition salts of the subject compounds are obviously moresuitable due to their increased water solubility.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form refers tophysically discrete units suitable as unitary dosages, each unitcontaining a predetermined quantity of active ingredient calculated toproduce the desired therapeutic effect in association with the requiredpharmaceutical carrier. Examples of such dosage unit forms are tablets(including scored or coated tablets), capsules, pills, powder packets,wafers, injectable solutions or suspensions and the like, and segregatedmultiples thereof.

The present invention also relates to a method of treating warm-bloodedanimals suffering from disease states related to an abnormal enzymaticor catalytic activity of PDE IV, and/or disease states related to aphysiologically detrimental excess of cytokines, in particular allergic,atopic and inflammatory diseases, more in particular asthmatic andatopic diseases, most particular atopic dermatitis. Said methodcomprises the administration of a therapeutically effective amount of acompound of formula (I) or a N-oxide form, a pharmaceutically acceptableacid or base addition salt or a stereochemically isomeric form thereofin admixture with a pharmaceutical carrier.

In general it is contemplated that an effective daily amount would befrom 0.01 mg/kg to 10 mg/kg body weight. It is evident that saideffective daily amount may be lowered or increased depending on theresponse of the treated subject and/or depending on the evaluation ofthe physician prescribing the compounds of the instant invention. Theeffective daily amount range mentioned hereinabove are thereforeguidelines only and are not intended to limit the scope or use of theinvention to any extent.

The following examples are intended to illustrate and not to limit thescope of the present invention.

Experimental Part

Of some compounds of formula (I) the absolute stereochemicalconfiguration was not experimentally determined. In those cases thestereochemically isomeric form which was first isolated is designated as"A" and the second as "B", without further reference to the actualstereochemical configuration.

Hereinafter, "THF" means tetrahydrofuran, "RT" means room temperature,"DMF" means N,N-dimethylformamide and "DIPE" means diisopropylether.

A. Preparation of the Intermediate Compounds

Example A.1

a) Potassium carbonate (0.0569 mol) was added dropwise to a mixture of4-difluoromethoxy-3-hydroxybenzaldehyde (0.053 mol) and(tetrahydro-3-furanol)-4-methylbenzenesulfonate (15.35 g) in DMF (100ml) under N₂ flow. The reaction mixture was stirred for 4 hours at 100°C. The mixture was cooled and a solution of(tetrahydro-3-furanol)-4-methylbenzenesulfonate (3.98 g) in DMF (40 ml)was added dropwise and the reaction mixture was stirred for 3 hours at100° C., then overnight at RT. The solvent was evaporated and theresidue was washed in a saturated aqueous Na₂ CO₃ solution, thenextracted with DIPE. The separated organic layer was dried, filtered,and the solvent was evaporated, yielding 17.77 g of(±)-4-(difluoromethoxy)-3-[(tetrahydro-3-furanyl)oxy]benzaldehyde(intermediate 1).

b) A sodium borohydride solution (0.0177 mol) was added portionwise to asolution of intermediate 1 (0.0532 mol) in methanol (100 ml), and thereaction mixture was stirred for 1 hour at RT. The solvent wasevaporated, the residue was washed with water, and extracted with CH₂Cl₂. The separated organic layer was dried, filtered, and the solventwas evaporated. The residue was purified by open column chromatographyover silica gel (eluent: CH₂ Cl₂ /2-propanone 96/4 and 90/10; CH₂ Cl₂/CH₃ OH 96/4). The pure fractions were collected and the solvent wasevaporated, yielding 11.3 g (81%) of(±)-4-(difluoromethoxy)-3-[(tetrahydro-3-furanyl)oxy]benzenemethanol(intermediate 2).

c) A solution of intermediate 2 (0.039 mol) in toluene (45 ml) was addeddropwise to a mixture of SOCl₂ (0.059 mol) and DMF (0.0019 mol) intoluene (75 ml), stirred at 40° C. The resulting reaction mixture wasstirred at 40° C., until HCl-gas evolution had stopped. The solvent wasevaporated and the residue was washed with a saturated aqueous NaHCO₃solution, and extracted with CH₂ Cl₂. The separated organic layer wasdried, filtered, and the solvent evaporated, yielding 10.59 g (96%) of(±)-4-(difluoromethoxy)-3-[(tetrahydro-3-furanyl)oxy]benzenemethanol(intermediate 3).

d) A mixture of KCN (0.076 mol) in H₂ O (4 ml), heated to 80° C., wasadded dropwise to a mixture of intermediate 3 (0.038 mol) in DMF (82.4ml), stirred at 60° C. The resulting reaction mixture was stirred for 30minutes at 60° C. The reaction mixture was cooled, washed with water,extracted with DIPE. The extract was dried, filtered, and the filtratewas evaporated, yielding 8.23 g (80%) of(±)-4-(difluoromethoxy)-3-[(tetrahydro-3-furanyl)oxy]benzeneacetonitrile(intermediate 4).

In a similar way, there were prepared:

3-(cyclopropylmethoxy)-4-methoxybenzeneacetonitrile (intermediate 5);

3-[(1,3-dihydro-2H-inden-2-yl)oxy]-4-methoxybenzeneacetonitrile(intermediate 6);

(±)-4-methoxy-3-[(tetrahydro-3-furanyl)oxy]benzeneacetonitrile(intermediate 7);

4-methoxy-3-[(5-phenylpentyl)oxy]benzeneacetonitrile (intermediate 8);

4-(difluoromethoxy)-3-[(5-phenylpentyl)oxy]benzeneacetonitrile(intermediate23).

Example A.2

a) N-(1-methylethyl)-2-propanamine lithium salt (0.0325 mol; 1 M in THF)was added dropwise and under N₂ flow to intermediate 4 (0.0309 mol) inTHF (70 ml), cooled to -78° C. The mixture was stirred for 30 minutes at-78° C. lodomethane iodide (0.034 mol) was added dropwise and thereaction mixture was stirred for 2 hours at RT. The mixture was quenchedwith a saturated aqueous NH₄ Cl solution, and extracted withethylacetate. The separated organic layer was dried, filtered, and thesolvent was evaporated. The residue was purified by short open columnchromatography over silica gel (eluent: CH₂ Cl₂), then by HPLC oversilica gel (eluent: hexane/ethylacetate 3/2). The pure fractions werecollected and the solvent, yielding 4.64 g (53%) of(±)-4-(difluoromethoxy)-alpha-methyl-3-[(tetrahydro-3-furanyl)oxy]benzeneacetonitrile(intermediate 9).

b) A mixture of intermediate 9 (0.0129 mol) in CH₃ OH/NH₃ (100 ml) washydrogenated at RT with Raney Nickel (3 g) as a catalyst. After uptakeof H₂, the catalyst was filtered off and the filtrate was evaporated,yielding 3.66 g (98%) of(±)-4-(difluoromethoxy)-β-methyl-3-[(tetrahydro-3-furanyl)oxy]benzeneethanamine(intermediate 10).

c) A mixture of intermediate 10 (0.0158 mol) and diphenylN-cyano-carbonimidate (0.0158 mol) in ethanol (60 ml) was stirredovernight at RT. The solvent was evaporated and the residue was purifiedby open column chromatography over silica gel (eluent:hexane/ethylacetate 3/2 and CH₂ Cl₂ /CH₃ OH 96/4, 90/10 and 85/5). Thepure fractions were collected and the solvent was evaporated, yielding5.11 g (74%) of (±)-phenylN-cyano-N-[2-[4-(difluoromethoxy)-3-[(tetrahydro-3-furanyl)oxy]phenyl]propyl]carbamimidate (intermediate 11).

d) A mixture of 2,2-dimethoxyethanamine (0.0129 mol),N,N-diethylethanamine (0.023 mol) and N,N-dimethyl-4-pyridinamine(0.0059 mol) in 1,4-dioxane (30 ml) was added to a solution ofintermediate 11 (0.0117 mol) in 1,4-dioxane (10 ml), stirred at RT. Thereaction mixture was stirred and refluxed overnight. The solvent wasevaporated and the residue was washed with water and 1 N NaOH, thenextracted with CH₂ Cl₂. The separated organic layer was dried, filtered,and the solvent was evaporated. The residue was purified by open columnchromatography over silica gel (eluent: CH₂ Cl₂ /CH₃ OH 96/4). The purefractions were collected and the solvent was evaporated, yielding 4.97 g(95%) of(±)-N"-cyano-N-[2-[4-(difluoromethoxy)-3-[(tetrahydro-3-furanyl)oxy]phenyl]propyl]-N'-(2,2-dimethoxyethyl)guanidine(intermediate 12).

In a similar way, there were prepared:

(±)-N"-cyano-N-[2-[3-(cyclopentyloxy)-4-methoxyphenyl]propyl]-N'-(2,2-dimethoxyethyl)guanidine(intermediate 13);

(±)-N"-cyano-N-[2-[3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl]propyl]-N'-(2,2-dimethoxyethyl)guanidine(intermediate 14);

N"-cyano-N-[2-[3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl]ethyl]-N'-(2,2-dimethoxyethyl)guanidine(intermediate 15);

(±)-N"-cyano-N-[2-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]propyl]-N'-(2,2-dimethoxyethyl)guanidine(intermediate 16);

(±)-N"-cyano-N-[2-[3-[(1,3-dihydro-2H-inden-2-yl)oxy]-4-methoxyphenyl]propyl]-N'-(2,2-dimethoxyethyl)guanidine(intermediate 17);

(+)-N"-cyano-N-[2-[3-(cyclopropylmethoxy)-4-methoxyphenyl]propyl]-N'-(2,2-dimethoxyethyl)guanidine(intermediate 18);

(±)-N"-cyano-N-(2,2-dimethoxyethyl)-N'-[2-[4-methoxy-3-[(5-phenylpentyl)oxy]phenyl]propyl]guanidine (intermediate 19);

(±)-N"-cyano-N-(2,2-dimethoxyethyl)-N'-[2-[4-methoxy-3-[(tetrahydro-3-furanyl)oxy]phenyl]propyl]guanidine(intermediate 20);

N"-cyano-N'-(2,2-dimethoxyethyl)-N-[2-[4-(difluoromethoxy)-3-[(5-phenylpentyl)oxy]phenyl]propyl]guanidine(intermediate24);

N"-cyano-N'-[2-[3-[(2,3-dihydro-1H-inden-2-yl)oxy]-4-methoxyphenyl]ethyl]-N-(2,2-dimethoxyethyl)guanidine(intermediate25)

(±)-N"-cyano-N-[2-[3-[2-(2,3-dihydro-1H-inden-2-yl)ethoxy]-4-methoxyphenyl]propyl]-N'-(2,2-dimethoxyethyl)guanidine (intermediate 27);

(±)-N"-cyano-N-[2-[3-[(2,3-dihydro-1H-inden-2-yl)oxy]-4-methoxyphenyl]-2-[(tetra-hydro-2H-pyran-2-yl)oxy]ethyl]-N'-(2,2-dimethoxyethyl)guanidine(intermediate 28).

Example A.3

a) A mixture of(±)-3-(cyclopentyloxy)-4-methoxy-β-methylbenzeneethanamine (0.029 mol),chloroacetonitrile (0.0146 mol) and sodium carbonate (0.0219 mol) in DMF(200 ml) was stirred for 5 hours at 60° C. The reaction mixture wasfiltered and the filtrate was evaporated. The residue was washed withwater, then extracted with 2-methoxy-2-methylpropane. The separatedorganic layer was dried, filtered, and the solvent was evaporated. Theresidue was purified by open column chromatography over silica gel(eluent: CH₂ Cl₂ ; CH₂ Cl₂ /2-propanone 96/4, and 90/10; then, CH₂ Cl₂/CH₃ OH 80/20). The pure fractions were collected and the solvent wasevaporated, yielding 3.24 g (77%) of(±)-[[2-[3-(cyclopentyloxy)-4-methoxyphenyl]propyl]amino]acetonitrile(intermediate 21).

b) A mixture of intermediate 21 (0.0117 mol) in NH₃ /CH₃ OH (60 ml) washydrogenated at RT with Raney Nickel (2 g) as a catalyst. After uptakeof H₂, the catalyst was filtered off and the filtrate was evaporated.The residue was treated with a 10% aqueous HCl solution, and thismixture was extracted with ethylacetate. The layers were separated. Theaqueous phase was basified, then extracted with ethylacetate. Theseparated organic layer was dried, filtered, and the solvent wasevaporated, yielding 2.71 g (75%) of(±)-N-[2-[3-(cyclopentyloxy)-4-methoxyphenyl]propyl]-1,2-ethanediamine(intermediate 22).

Example A.4

a) A mixture of 6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (0.03544 mol),3-hydroxy-4-methoxybenzaldehyde (0.0322 mol) and triphenylphosphine(0.0322 mol) in THF (100 ml) was stirred at 5° C. under N₂ atmosphere.Bis(1-methylethyl) diazenedicarboxylate (0.0322 mol) was added dropwiseand the resulting reaction mixture was stirred for 12 hours at RT. Thesolvent was evaporated. CH₂ Cl₂ was added to the residue. The mixturewas washed with water, dried, filtered and the solvent was evaporated.The residue was purified over silica gel on a glass filter (eluent: CH₂Cl₂ /CH₃ OH from 100/0 to 98.5/1.5). The desired fractions werecollected and the solvent was evaporated. The residue was dissolved in2-propanol and converted into the hydrochloric acid salt (1:1) withHCl/2-propanol. The solvent was evaporated. The residue was stirred inDIPE, filtered off and dried, yielding 8.2 g (83%) of3-[(5,6-dihydro-7H-pyrindin-7-yl)oxy]-4-methoxybenzaldehydehydrochloride (intermediate 34).

b) A solution of trimethylsilanecarbonitrile, (0.1472 mol) in CH₂ Cl₂(60 ml) was added dropwise to a mixture of3-[(2,3-dihydro-1H-inden-2-yl)oxy]-4-methoxy-benzaldehyde (0.1227 mol)and Zinc iodide (0.0061 mol) in CH₂ Cl₂ (240 ml). The resulting reactionmixture was stirred for one hour at RT. The crude reaction mixture waswashed with water and brine, then extracted with CH₂ Cl₂. The separatedorganic layer was dried, filtered, and the solvent was evaporated. Theresidue was crystallized from DIPE. The precipitate was filtered off anddried, yielding 37.39 g (83%) of(±)-3-[(2,3-dihydro-1H-inden-2-yl)oxy]-4-methoxy-α-[(trimethylsilyl)oxy]benzeneacetonitrile(intermediate 29).

c) Intermediate 29 (0.1116 mol) was dissolved in methanol. HCl (3 N, 25ml) was added. The mixture was stirred for 5 minutes. Most of thesolvent was evaporated and CH₂ Cl₂ was added. The organic layer wasseparated, washed with a saturated aqueous NaHCO₃ solution, dried,filtered and the solvent was evaporated. The residue was dissolved inCH₂ Cl₂ (350 ml). 3,4-dihydro-2H-pyrane (0.2231 mol) and4-methylbenzenesulfonic acid (catalytic quantity) were added and theresulting reaction mixture was stirred overnight at RT. The mixture waswashed with a saturated aqueous NaHCO₃ solution, dried, filtered and thesolvent was evaporated. The residue was purified by short open columnchromatography over silica gel (eluent: hexanes/ethylacetate 9/1, then8/2). The desired fractions were collected and the solvent wasevaporated, yielding: 28.01 g (66%) of(±)-3-[(2,3-dihydro-1H-inden-2-yl)oxy]-4-methoxy-α-[(tetrahydro-2H-pyran-2-yl)oxy]benzeneacetonitrile(intermediate 30).

Example A.5

a) A solution of bis(1,1-dimethylethyl) dicarbonoate (1.268 mol) in CH₂Cl₂ (1800 ml) was added dropwise to a solution of(±)-3-[(2,3-dihydro-1H-inden-2-yl)oxy]-4-methoxy-β-methylbenzeneethanamine(1.208 mol) in C (1800 ml). The mixture was stirred at RT for 2 hours.The solvent was evaporated. The residue was stirred in hexane, filteredoff and dried, yielding 420 g of (±)-1,1-dimethylethyl[2-[3-[(2,3-dihydro-1H-inden-2-yl)oxy]-4-methoxyphenyl]propyl]carbamate(intermediate 31).

b) Intermediate 31 (1.056 mol) was purified and separated by chiralcolumn chromatography over Chiralpack AD (eluent: hexane/C₂ H₅ OH/CH₃ OH90/10/10). The desired fraction group was collected and the solvent wasevaporated, yielding 268 g 1,1-dimethylethylB-[2-[3-[(2,3-dihydro-1H-inden-2-yl)oxy]-4-methoxyphenyl]-propyl]-carbamate(intermediate 32).

c) A mixture of intermediate 32 (0.67 mol) in HCl (670 ml; 6N) andmethanol (2700 ml) was stirred and refluxed for 90 minutes. The solventwas evaporated. The residue was taken up in CH₂ Cl₂. The organicsolution was washed with H₂ O (1000 ml) and a saturated NaHCO₃ solution.The organic layer was separated, dried, filtered and the solvent wasevaporated, yielding 158g (99%) of(B)-3-[(2,3-dihydro-1H-inden-2-yl)oxy]-4-methoxy-β-methylbenzeneethanamine(intermediate 33). Intermediate 33 was further reacted according to theprocedure described in example A.2.b to A.2.d to form(B)-N"-cyano-N-[2-[3-[(2,3-dihydro-1H-inden-2-yl)oxy]-4-methoxyphenyl]propyl]-N'-(2,2-dimethoxyethyl)guanidine(intermediate 26).

B. Preparation of the Compounds of Formula (I)

Example B.1

A mixture of intermediate 22 (0.0068 mol) and dimethylcyanocarbonimidodithioate (0.0068 mol) in ethanol (20 ml) was stirredand refluxed for 2 days. The solvent was evaporated and the residue wasfirst purified by short open column chromatography over silica gel(eluent: CH₂ Cl₂, CH₂ Cl₂ /CH₃ OH 96/4 and 90/10), then twice by HPLC (1eluent: CH₂ Cl₂ /CH₃ OH 90/10 and 2. Eluent: CH₂ Cl₂ /CH₃ OH 96/4). Thepure fractions were collected and the solvent was evaporated, yielding0.3 g (13%) of(±)-[1-[2-[3-(cyclopentyloxy)-4-methoxyphenyl]propyl]-2-imidazolidinylidene]cyanamide (compound 1).

Example B.2

HCl 0.5 N (0.0162 mol) was added dropwise to a solution of intermediate12 (0.0108 mol) in 1,4-dioxane (20 ml), stirred and cooled in anice-bath. The reaction mixture was stirred for 2 days at RT. (As analternative, 1,4-dioxane may be replaced by THF and the reaction mixturemay be refluxed for 1 hour instead of stirring 2 days at RT). Thereaction mixture was treated with water, alkalized with a dilute NaOHsolution, then extracted with ethylacetate. The separated organic layerwas dried, filtered, and the solvent was evaporated. The residue waspurified by open column chromatography over silica gel (eluent: CH₂ C₂/2-propanone 96/4; CH₂ Cl₂ /CH₃ OH 96/4) and twice by HPLC over silicagel (1. Eluent: CH₂ Cl₂ /CH₃ OH 96/4 and 2. Eluent: CH₂ Cl₂ /CH₃ OH97/3). The pure fractions were collected and the solvent was evaporated,yielding 0.64 g (15%) of(±)-[1-[2-[4-(difluoromethoxy)-3-[(tetrahydro-3-furanyl)oxy]phenyl]-propyl]-1,3-dihydro-2H-imidazol-2-ylidene]cyanamide(compound 2; mp. 67.8° C.).

Example B.3

a) Compound 7 (0.00644 mol) was separated into its enantiomers by chiralcolumn chromatography over Chiralpak AD (20 μm, 250 g, 5 cm, flow: 60ml/min; eluent: hexane/ethanol/methanol 80/15/5). Two desired fractiongroups were collected. The solvent of the first (A)-fraction group wasevaporated. The residue was stirred in DIPE, filtered off, washed withDIPE, then dried. The residue was further purified by columnchromatography over Kromasil silica gel (200 g, 5 μm, eluent: CH₂ Cl₂/CH₃ OH 100/0, after 30 minutes, 90/10). The pure fractions werecollected and the solvent was evaporated. The residue was stirred inDIPE, filtered off, washed with DIPE, then dried, yielding 0.39 g (50%)of(+)-(A)-[1-[2-[3-[(2,3-dihydro-1H-inden-2-yl)oxy]-4-methoxy-phenyl]-propyl]-1H-imidazol-2-yl]cyanamide;[α]_(D) ²⁰ =+95.46° (c=0.1% in CH₃ OH) (compound 16). The solvent of thesecond (B)-fraction group was evaporated. The residue was stirred inDIPE, filtered off, washed with DIPE, then dried. The residue waspurified by column chromatography over Kromasil silica gel (200 g, 5 μm,eluent: CH₂ Cl₂ /CH₃ OH 100/0, after 30 minutes, 90/10). The purefractions were collected and the solvent was evaporated. The residue wasstirred in DIPE, filtered off, washed with DIPE, then dried, yielding0.5 g (90%) of(-)-(B)-[1-[2-[3-[(2,3-dihydro-1H-inden-2-yl)oxy]-4-methoxy-phenyl]propyl]-1H-imidazol-2-yl]cyanamide;[α]_(D) ²⁰ =-109.04° (c=0.1% in CH₃ OH) (compound 17).

b) A mixture of compound 17 (0.0026 mol) in DMF (40 ml) was stirred at0° C. Sodium hydride (0.0028 mol; 60%) was added and the mixture wasstirred for 30 minutes at 0° C. and for 30 minutes at RT. A solution ofbromomethylbenzene (0.0028 mol) in DMF (10 ml) was added dropwise andthe resulting reaction mixture was stirred for 3 hours at RT. Thesolvent was evaporated, toluene was added and azeotroped on the rotaryevaporator. The residue was taken up into CH₂ Cl₂. Water was added. Theorganic layer was separated, dried, filtered and the solvent wasevaporated. The residue was purified by short column chromatography oversilica gel (eluent: CH₂ Cl₂ /CH₃ OH 98/2). The desired fractions werecollected and thesolvent was evaporated, yielding 0.7 g (63%) of(B)-[1-[2-[3-[(2,3-dihydro-1H-inden-2-yl)oxy]-4-methoxy-phenyl]propyl]-3-phenylmethyl-1H-imidazol-2-yl]cyanamide(compound 23).

Example B.4

HCl (0.0268 mol; 0.5N) was added to a solution of intermediate 28(0.0179 mol) in THF (250 ml), stirred and cooled on an ice-bath. Thereaction mixture was stirred and refluxed for 1.5 hours, then cooled onan ice-bath. The mixture was partitioned between water and ethylacetate,and alkalized with solid Na₂ CO₃. The organic layer was separated,dried, filtered, and the solvent was evaporated. The residue waspurified by short open column chromatography over silica gel (eluent:CH₂ Cl₂ /CH₃ OH 97/3, then 95/5). The desired pure fraction group wascollected. The solvent was evaporated and the residue was crystallizedfrom CH₃ CN, filtered off and dried, yielding (35%) of(±)-[1-[2-[3-[(2,3-dihydro-1H-inden-2-yl)oxy]-4-methoxyphenyl]-2-hydroxyethyl]-1,3-dihydro-2H-imidazol-2-ylidine]cyanamide(compound 21).

Table 1 lists compounds of formula (I) that were prepared according toone of the above examples.

                                      TABLE 1                                     __________________________________________________________________________      #STR13##                                                                       -                                                                          Co.                                                                              Ex.                                       Physical data                      No. No. R.sup.1 R.sup.2 R.sup.4 L --A--B-- mp in ° C.                __________________________________________________________________________     1 B.1  cyclopentyl     CH.sub.3                                                                         CH.sub.3                                                                         H      --CH.sub.2 --CH.sub.2 --                                                              (E + Z)                             2 B.2 3-tetrahydrofuranyl CHF.sub.2 CH.sub.3 H --CH═CH-- 67.8.degre                                                 e. C.                               3 B.2 cyclopentyl CH.sub.3 CH.sub.3 H --CH═CH-- 101.3° C.                                                      4 B.2 cyclopentyl CHF.sub.2                                                  CH.sub.3 H --CH═CH--                                                     133° C.                      5 B.2 cyclopentyl CHF.sub.2 H H --CH═CH-- 158.9° C.                                                            6 B.2 cyclopropylmethyl                                                     CHF.sub.2 CH.sub.3 H                                                          --CH═CH-- liquid                                                            -  7 B.2                                                                      CH.sub.3 CH.sub.3 H                                                         --CH═CH-- 87.5°                                                    C.                                  -  8 B.2 cyclopropylmethyl CH.sub.3 CH.sub.3 H --CH═CH-- 66.2.degre                                                 e. C.                               9 B.2 phenylpentyl CH.sub.3 CH.sub.3 H --CH═CH-- --                      10 B.2 3-tetrahydrofuranyl CH.sub.3 CH.sub.3 H --CH═CH-- 73.4.degree                                                 . C.                               11 B.2 phenylpentyl CHF.sub.2 CH.sub.3 H --CH═CH-- --                     12 B.3 cyclopentyl CH.sub.3 CH.sub.3 H --CH═CH-- (A)                      13 B.3 cyclopentyl CH.sub.3 CH.sub.3 H --CH═CH-- (B)                      14 B.3 cyclopropylmethyl CH.sub.3 CH.sub.3 H --CH═CH-- (A)                15 B.3 cyclopropylmethyl CH.sub.3 CH.sub.3 H --CH═CH-- (B)                 - 16 B.3                                                                                                                  CH.sub.3 CH.sub.3 H                                                         --CH═CH-- (A)                   - 17 B.2 or B.3                                                                                                           CH.sub.3 CH.sub.3 H                                                         --CH═CH-- (B); 138.7.degr                                                 ee. C.                              - 18 B.3 phenylpentyl CH.sub.3 CH.sub.3 H --CH═CH-- (A)                  19 B.3 phenylpentyl CH.sub.3 CH.sub.3 H --CH═CH-- (B)                      - 20 B.2                                                                                                                  CH.sub.3 H H --CH═CH--                                                  --                                  - 21 B.4                                                                                                                  CH.sub.3 OH H --CH═CH--                                                  mp. 179.9° C.                                                           - 22 B.2                                                                      CH.sub.3 CH.sub.3 H                                                         --CH═CH-- mp. 115.3.degre                                                 e. C.                               - 23 B.3b                                                                                                                 CH.sub.3 CH.sub.3 phenylmet                                                 hyl --CH═CH-- (B)                                                           - 24 B.3b                                                                     CH.sub.3 CH.sub.3 C(═O)                                                 OC.sub.2 H.sub.5 --CH═CH-                                                 - (B)                               - 25 B.3b                                                                                                                 CH.sub.3 CH.sub.3 diphenylm                                                 ethyl --CH═CH-- (B)                                                         - 26 B.2                                                                      CH.sub.3 H H --CH═CH--                                                  --                               __________________________________________________________________________

C. Pharmacological Example

Example C.1: Inhibition of Recombinant Human Mononuclear Lymphocyte(MNL) Phosphodiesterase Type IV B Produced in Insect Cells with aBaculovirus Vector

The alleviating and/or curing effect of the instant compounds onallergic and atopic diseases was assessed by an in vitro assay system todetect an inhibiting effect on the recombinant human MNLphosphodiesterase type IV B.

Seventy-two hours after infection with recombinant baculovirus, theinsect cells were harvested and pelleted at 500 g for 5 minutes. Thecells were lysed in 10 ml lysis-buffer consisting of 20 mM Tris, 10 mMEGTA, 2 mM Na₂ EDTA, 1% Triton-X-100, 1 mM Na₃ VO₄, 10 mM NaF, 2 μg/mlof leupeptine, pepstatine and aprotinine, 0.3 μg/ml benzamidine and 100μg/ml TPCK pH 7.5. After 5 minutes on ice, solubilized cells werecentrifuged at 4000 rpm for 15 minutes at 4° C. The resultingsupernatant was filtered through a 0.45 μm filter (Millipore) andbrought to TBS buffer (50 mM Tris, 150 mM NaCl pH 7.4).

The supernatant containing phosphodiesterase (PDE) type IV B, wassubsequently loaded onto a 5 ml anti-FLAG-M₂ affinity gel column,previously activated with 5 ml 100 mM glycine pH 3.5 and equilibratedwith 20 ml 50 mM Tris, 150 mM NaCl pH 7.4. After washing the column withequilibration buffer, PDE IV was eluted in 1.5 ml fractions containing37.5 μl 1M Tris pH 8. The fractions were dialyzed overnight against 20mM Tris, 2 mM Na₂ EDTA and 400 mM NaCl pH 7.5 and tested for PDE IVactivity. Indentification was done on SDS PAGE and Western Blot(anti-FLAG-M₂). Active fractions were pooled, brought to 10% glyceroland stored at -70° C.

The incubation mixture (pH 8) (200 μl) contained 20 mM Tris, 10 mMmagnesium sulphate, 0.8 μM ³ H-cAMP (310 mCi/mmole) and thephosphodiesterase type IV, the amount depending on the enzymaticactivity. A protein concentration was chosen that showed a linearincrease of phosphodiesterase activity during an incubation period ofmaximum 10 minutes at 37° C. and where less than 10% of the initialsubstrate was hydrolyzed. When the effect of different compounds onphosphodiesterase activity was tested, the medium without cAMP wasincubated with the compound(s) or its carrier (DMSO-1% finalconcentration) for 5 minutes. The enzymatic reaction was started byaddition of ³ H-cAMP and stopped 10 minutes later after transferring themicrotiter-plate in a waterbath at 100° C. for 5 minutes. After coolingto room temperature, alkaline phosphatase (0.25 μg/ml) was added and themixture was incubated at 37° C. for 20 min. 100 μl of the mixture wassubsequently applied to a GF-B filter-microtiter-plate (Millipore)filled with 300 μl DEAE-Sephadex-A25 suspension. The plate was washed 3times with 75 μl 20 mM Tris pH 7.5 and the filtrates were collected forcounting in the Packard Top Count scintillation counter.

The inhibiting effect of the present compounds on recombinant human MNLphosphodiesterase PDE IV B was measured at different concentrations ofthe instant compounds. The IC₅₀ values (expressed in M) were calculatedgraphically from the thus obtained inhibition values and are listed inTable 2.

                  TABLE 2                                                         ______________________________________                                        Comp. No.     IC.sub.50 (in 10.sup.-8 M)                                      ______________________________________                                        1             33.0                                                              2            10.0                                                             3            3.00                                                             4            1.53                                                             5            2.66                                                             6            2.24                                                             7            1.90                                                             8            5.65                                                             9            3.61                                                             10           19.6                                                             11          3.27                                                              12          2.19                                                              13          2.22                                                              14          2.72                                                              15          3.35                                                              16          1.80                                                              17          3.00                                                              18          4.09                                                              19          3.75                                                              20          7.65                                                            ______________________________________                                    

D. Composition Examples

The following formulations exemplify typical pharmaceutical compositionssuitable for systemic or topical administration to animal and humansubjects in accordance with the present invention.

"Active ingredient" (A.I.) as used throughout these examples relates toa compound of formula (I) or a pharmaceutically acceptable addition saltthereof.

Example D. 1: Film-Coated Tablets

Preparation of Tablet Core

A mixture of 100 g of the A.I., 570 g lactose and 200 g starch was mixedwell and thereafter humidified with a solution of 5 g sodium dodecylsulfate and 10 g polyvinyl-pyrrolidone in about 200 ml of water. The wetpowder mixture was sieved, dried and sieved again. Then there was added100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil.The whole was mixed well and compressed into tablets, giving 10.000tablets, each comprising 10 mg of the active ingredient.

Coating

To a solution of 10 g methyl cellulose in 75 ml of denaturated ethanolthere was added a solution of 5 g of ethyl cellulose in 150 ml ofdichloromethane. Then there were added 75 ml of dichloromethane and 2.5ml 1,2,3-propanetriol. 10 g of polyethylene glycol was molten anddissolved in 75 ml of dichloromethane. The latter solution was added tothe former and then there were added 2.5 g of magnesium octadecanoate, 5g of polyvinylpyrrolidone and 30 ml of concentrated color suspension andthe whole was homogenated. The tablet cores were coated with the thusobtained mixture in a coating apparatus.

Example D.2: 2% Topical Cream

To a solution of 200 mg hydroxypropyl β-cyclodextrine in purified wateris added 20 mg of A.I. while stirring. Hydrochloric acid is added untilcomplete dissolution and next sodium hydroxide is added until pH 6.0.While stirring, 50 mg glycerol and 35 mg polysorbate 60 are added andthe mixture is heated to 70° C. The resulting mixture is added to amixture of 100 mg mineral oil, 20 mg stearyl alcohol, 20 mg cetylalcohol, 20 mg glycerol monostearate and 15 mg sorbate 60 having atemperature of 70° C. while mixing slowly. After cooling down to below25° C., the rest of the purified water q.s. ad 1 g is added and themixture is mixed to homogenous.

What is claimed is:
 1. A compound having the formula ##STR24## a N-oxideform, a pharmaceutically acceptable acid or base addition salt or astereochemically isomeric form thereof, wherein:R¹ and R² eachindependently are hydrogen; C₁₋₆ alkyl; difluoromethyl; trifluoromethyl;C₃₋₆ cycloalkyl; a saturated 5-, 6- or 7-membered heterocycle containingone or two heteroatoms selected from oxygen, sulfur or nitrogen;indanyl; 6,7-dihydro-5H-cyclopentapyridinyl; bicyclo[2.2.1]-2-heptenyl;bicyclo[2.2.1]heptanyl; C₁₋₆ alkylsulfonyl; arylsulfonyl; or C₁₋₁₀ alkylsubstituted with one or two substituents each independently selectedfrom aryl, pyridinyl, thienyl, furanyl, indanyl,6,7-dihydro-5H-cyclopentapyridinyl, C₃₋₇ cycloalkyl and a saturated 5-,6- or 7-membered heterocycle containing one or two heteroatoms selectedfrom oxygen, sulfur or nitrogen; R³ is hydrogen, halo or C₁₋₆ alkyloxy;R⁴ is hydrogen; halo; C₁₋₆ alkyl; trifluoromethyl; C₃₋₆ cycloalkyl;carboxyl; C₁₋₄ alkyloxycarbonyl; C₃₋₆ cycloalkylaminocarbonyl; aryl;Het¹ ; or C₁₋₆ alkyl substituted with cyano, amino, hydroxy, C₁₋₄alkylcarbonylamino, aryl or Het¹ ; or R⁴ is a radical of formula:

    --O--R.sup.7                                               (a- 1); or

    --NH--R.sup.8                                              (a- 2);

wherein R⁷ is hydrogen; C₁₋₆ alkyl; C₁₋₆ alkyl substituted with hydroxy,carboxyl, C₁₋₄ alkyloxycarbonyl, amino, mono- or di(C₁₋₄ alkyl)amino,Het¹ or aryl;R⁸ is hydrogen; C₁₋₆ alkyl; C₁₋₄ alkylcarbonyl; C₁₋₆ alkylsubstituted with hydroxy, carboxyl, C₁₋₄ alkyloxycarbonyl, amino, mono-or di(C₁₋₄ alkyl)amino, Het¹ or aryl; R⁵ is hydrogen, halo, hydroxy,C₁₋₆ alkyl or C₁₋₆ alkyloxy; or R⁴ and R⁵ taken together form a bivalentradical of formula:

    --(CH.sub.2).sub.n --                                      (b-1);

    --CH.sub.2 --CH.sub.2 --O--CH.sub.2 --CH.sub.2 --          (b-2);

    --CH.sub.2 --CH.sub.2 --N(R.sup.9)--CH.sub.2 --CH.sub.2 -- (b-3); or

    --CH.sub.2 --CH═CH--CH.sub.2 --                        (b-4);

wherein n is 2, 3, 4 or 5;R⁹ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkylsulfonylor p-toluenesulfonyl; R⁶ is a hydrogen or C₁₋₄ alkyl; or R⁴ and R⁶ takentogether may form a bivalent radical of formula --(CH₂)_(m) --; whereinm is 1, 2, 3 or 4; --A--B-- is a bivalent radical of formula:

    --CR.sup.10 ═CR.sup.11 --                              (c-1); or

    --CHR.sup.10 --CHR.sup.11 --                               (c-2);

wherein each R¹⁰ and R¹¹ independently is hydrogen or C₁₋₄ alkyl; and Lis hydrogen; C₁₋₆ alkyl; C₁₋₆ alkylcarbonyl; C₁₋₆ alkyloxycarbonyl; C₁₋₆alkyl substituted with one or two substituents selected from the groupconsisting of hydroxy, C₁₋₄ alkyloxy, C₁₋₄ alkyloxycarbonyl, mono- anddi(C₁₋₄ alkyl)amino, aryl and Het² ; C₃₋₆ alkenyl; C₃₋₆ alkenylsubstituted with aryl; piperidinyl; piperidinyl substituted with C₁₋₄alkyl or arylC₁₋₄ alkyl; C₁₋₆ alkylsulfonyl or arylsulfonyl; aryl isphenyl or phenyl substituted with one, two or three substituentsselected from halo, hydroxy, C₁₋₄ alkyl, C₁₋₄ alkyloxy, C₃₋₆ cycloalkyl,trifluoromethyl, amino, nitro, carboxyl, C₁₋₄ alkyloxycarbonyl and C₁₋₄alkylcarbonylamino; Het¹ is pyridinyl; pyridinyl substituted with C₁₋₄alkyl; furanyl; furanyl substituted with C₁₋₄ alkyl; thienyl; thienylsubstituted with C₁₋₄ alkylcarbonylamino; hydroxypyridinyl,hydroxypyridinyl substituted with C₁₋₄ alkyl or C₁₋₄ alkoxy-C₁₋₄ alkyl;imidazolyl; imidazolyl substituted with C₁₋₄ alkyl; thiazolyl; thiazolylsubstituted with C₁₋₄ alkyl; oxazolyl; oxazolyl substituted with C₁₋₄alkyl; isoquinolinyl; isoquinolinyl substituted with C₁₋₄ alkyl;quinolinonyl, quinolinonyl substituted with C₁₋₄ alkyl; morpholinyl;piperidinyl; piperidinyl substituted with C₁₋₄ alkyl, C₁₋₄alkyloxycarbonyl or arylC₁₋₄ alkyl; piperazinyl; piperazinyl substitutedwith C₁₋₄ alkyl, C₁₋₄ alkyloxycarbonyl or arylC₁₋₄ alkyl; and Het² ismorpholinyl; piperidinyl; piperidinyl substituted with C₁₋₄ alkyl orarylC₁₋₄ alkyl; piperazinyl; piperazinyl substituted with C₁₋₄ alkyl orarylC₁₋₄ alkyl; pyridinyl; pyridinyl substituted with C₁₋₄ alkyl;furanyl; furanyl substituted with C₁₋₄ alkyl; thienyl or thienylsubstituted with C₁₋₄ alkyl or C₁₋₄ alkylcarbonylamino.
 2. A compoundaccording to claim 1 wherein R¹ and R² each independently are hydrogen;C₁₋₆ alkyl; difluoromethyl; trifluoromethyl; C₃₋₆ cycloalkyl; asaturated 5-, 6- or 7-membered heterocycle containing one or twoheteroatoms selected from oxygen, sulfur or nitrogen; indanyl;bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl; C₁₋₆ alkylsulfonyl;arylsulfonyl; or C₁₋₁₀ alkyl substituted with one or two substituentseach independently selected from aryl, pyridinyl, thienyl, furanyl, C₃₋₇cycloalkyl and a saturated 5-, 6- or 7-membered heterocycle containingone or two heteroatoms selected from oxygen, sulfur or nitrogen.
 3. Acompound according to claim 1 wherein R¹ and R² are each independentlyC₁₋₆ alkyl; C₃₋₆ cycloalkyl; difluoromethyl; a saturated 5-, 6- or7-membered heterocycle containing one or two heteroatoms selected fromoxygen, sulfur or nitrogen; indanyl; or C₁₋₁₀ alkyl substituted witharyl, indanyl, 6,7-dihydro-5H-cyclopentapyridinyl or C₃₋₆ cycloalkyl. 4.A compound according to claim 1 wherein R⁴ is C₁₋₆ alkyl.
 5. A compoundaccording to claim 1 wherein R¹ is cyclopentyl, tetrahydrofuranyl,cyclopropylmethyl, 5-phenylpentyl, 6,7-dihydro-5H-cyclopenta[b]pyridinylor indanyl; R² is methyl or difluoromethyl; and R³, R⁵, R⁶, R¹⁰, R¹¹ andL are hydrogen.
 6. A compound according to claim 1 wherein the compoundis[1-[2-[4-(difluoromethoxy)-3-[(tetrahydro-3-furanyl)oxy]phenyl]propyl]-1,3-dihydro-2H-imidazol-2-ylidene]cyanamide;and[1-[2-[4-(methoxy)-3-[(1,3-dihydro-2H-inden-2-yl)oxy]phenyl]propyl]-1,3-dihydro-2H-imidazol-2-ylidene]cyanamide,or a N-oxide, a stereochemically isomeric form or a pharmaceuticallyacceptable additon salt thereof.
 7. A composition comprising apharmaceutically acceptable carrier, and as active ingredient atherapeutically effective amount of a compound as claimed in claim
 1. 8.A process of preparing a composition comprising intimately mixing apharmaceutically acceptable carrier with a therapeutically effectiveamount of a compound as claimed in claim
 1. 9. A method of treating awarm-blooded animal suffering from an asthmatic or atopic diseasecomprising administering to the warm-blooded animal a therapeuticallyeffective amount of the compound of claim 1.